1 ABSTRACT 2 3 and cause asthma exacerbations. Studies have reported a higher prevalence of inflammatory lung disease in 4 women than men, but the mechanisms underlying these disparities are still unknown. Although the female 5 lung, as compared to the male lung, is exposed to increased levels of estrogen and progesterone from both 6 physiological and environmental sources, it is not known whether the combination of sex hormones and ozone 7 can affect lung health. In this context, high levels of ozone and female gender are negative prognostic 8 indicators for increased morbidity and mortality from chronic respiratory disease. 9 The overall objectives of this K01 proposal are to provide additional training and laboratory expertise to the 10 candidate, while she investigates mechanisms of ozone-induced inflammation in the male and female lung. 11 The candidate is a well-qualified junior scientist with a strong track record of commitment to academic 12 research. She has previously engaged in a wide variety of research projects, ranging from endocrinology and 13 biochemistry to immunology and lung physiology, and she has demonstrated productivity and potential for 14 independence. Her long term career goal is to develop into an independent and productive scientist who 15 investigates lung disease-relevant research with a creative and scientifically rigorous methodology. Through an 16 integrated approach, this project will promote the candidate's scientific and career development with guidance 17 from senior and experienced mentors, a scientific advisory committee comprised of experts in various aspects 18 of the proposed work, and additional academic and hands-on training to acquire new research expertise. The 19 Pennsylvania State University College of Medicine offers a unique environment to promote the success of the 20 candidate, including a financial commitment and protection of research time, senior faculty with expertise in the 21 research area, a collaborative and nurturing environment, and access to specialized resources, equipment, 22 and facilities necessary to complete the project. The candidate is a faculty member of the Departments of 23 Pediatrics and Biochemistry and Molecular Biology, where she has access to specialized expertise in the areas 24 of lung disease research from basic and clinical investigators of diverse backgrounds. 25 The central hypothesis of the proposed research plan is that both male and female sex hormones can 26 modulate ozone-induced inflammatory responses in the lung. Through a multidisciplinary approach, this 27 proposal will test this hypothesis via the following aims: 1) to characterize sex differences in lung function and 28 inflammation in response to ozone exposure, 2) to determine the role of sex hormones in ozone-induced lung 29 inflammation, and 3) to evaluate the effects of ozone and sex hormones in asthmatic inflammation. Although 30 previous clinical studies have indicated that the hormonal status can affect asthma exacerbations in women, 31 this is the first study to examine the specific roles of male and female sex hormones in ozone-induced 32 inflammation in the lungs of both normal and asthmatic mice. Together, the proposed studies will promote the 33 scientific development of the candidate and increase the understanding of the role of sex hormones in the 34 inflammatory response to a major air pollutant. As ambient ozone levels are anticipated to rise with climate 35 change, ozone-related asthma emergency room visits are expected to increase. Therefore, an improved 36 understanding of the role of sex hormones in the pathogenesis of asthmatic inflammation is of high clinical 37 significance, and will open the door for discovery of new gender specific therapeutic targets. 38 Ozone is a major component of urban air pollution known to affect lung function, increase airway inflammation,